Comparing the association of two metabolic syndrome definitions, NCEP ATP III and IDF, with the risk of developing atherosclerotic cardiovascular disease: An analytical cross‐sectional study

Abstract Introduction Atherosclerotic cardiovascular diseases (ASCVD) are significant sources of mortality and morbidity with substantial economic implications and preventive measures play key roles in this regard. Metabolic syndrome (MetS) is a common condition, and its association with ASCVD and mortality has made it clinically important. However, controversies persist regarding the best definition for MetS. Here in, we investigated the ability of the International Diabetes Federation (IDF) and the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) in the prediction of ASCVD incidence. Methods We conducted an investigation on individuals diagnosed with MetS as part of the “Kerman Coronary Artery Diseases Risk Factor Study” (KERCADRS). This study was a cohort study conducted on a population aged 15–75 years residing in Kerman, Iran to assess the risk of ASCVD. We employed ACC/AHA ASCVD Risk Estimator for predicting ASCVD occurrence in the future and then compared the results with different definitions of MetS including IDF and NCEP ATP III. Results Patients with MetS consistent with NCEP ATP III had higher ASCVD risk scores than those with IDF (10.63 ± 10.989 vs. 9.50 ± 9.357). NCEP ATP III had better overall performance in terms of specificity, accuracy, sensitivity and positive and negative predictive values especially in higher ASCVD risk score categories. The agreement between IDF and NCEP ATP III was none to slight (Cohen's Kappa <0.2) except for IDF in the group of ASCVD >30%, which revealed no agreement (Cohen's Kappa = 0). Conclusion NCEP ATP III has better overall performance compared to IDF. The ability of NCEP ATP III increases as the ASCVD risk score goes higher. IDF may be useful in primary screening and patients with lower ASCVD risk scores.


| INTRODUC TI ON
Atherosclerotic cardiovascular diseases (ASCVD) are the number one cause of mortality and morbidity globally. 1In 2020, almost 19 million people died from ASCVD. 2 The economic burden of ASCVD is substantial, and it's still increasing.Prevention is a crucial factor and can be achieved through practicing healthy habits: physical activity, healthy diets, non-smoking, reduced alcohol consumption and reduced stress. 3esity-associated cardiovascular risk factors including abdominal obesity, hypertriglyceridemia, decreased high-density lipoprotein (HDL), high blood pressure, and/or impaired glucose tolerance, are the elements of metabolic syndrome (MetS).The prevalence ranges from 20%-25% in adults and 0%-19.2% in children; up to 80% of diabetic patients can have MetS. 4The trend is also rising: the prevalence of MetS in the United States (US) adults has increased from 25.3% in 1988-1994 to 34.2% in 2007-2012. 5High prevalence, rising trend and association with ASCVD and mortality have made MetS a clinically important issue. 6ltiple definitions are available for MetS including World Health Assessing baseline ASCVD risk using ASCVD risk assessment tools is the beginning of the foundation of preventive cardiology.
By using the ASCVD risk assessment tools, we can determine the risk of developing ASCVD in individuals and try to prevent ASCVD in them.Usually, people with low risk are encouraged to do lifestyle modifications, and those with higher risks are recommended to have both lifestyle modifications and pharmacologic therapy. 13ASCVD risk score 14 is one of these tools provided by the American College of Cardiology (ACC)/American Heart Association (AHA).The score is the result of evaluating the risk of having ASCVD in 10 years.
Due to the discrepancy in the literature between different definitions of MetS and different populations, we decided to conduct a cross-sectional study to find out whether IDF or NCEP ATP III definition can better predict the risk of ASCVD in the Iranian population.

| Participants and procedures
We conducted an analytical cross-sectional study to compare the association of IDF with NCEP ATP III with ASCVD incidence.The population consisted of all the individuals with the diagnosis of MetS in the "Kerman Coronary Artery Diseases Risk Factor Study" (KERCADRS), 15 which was a cohort study performed on the pop- Dissatisfaction with participation in the study and not completing the questionnaire were the exclusion criteria.By using simple random sampling method, two groups with MetS based on IDF and NCEP ATP III definitions were selected and matched in terms of age, gender and cigarette smoking (Table 1).

| Measures
We used ACC/AHA ASCVD Risk Estimator 16 on the Assessment of Cardiovascular Risk for predicting ASCVD occurrence in the future.

| Statistical analysis
SPSS version 18 was our statistical analysis software.For descriptive statistics frequency, relative frequency, and mean were used.

K E Y W O R D S
atherosclerotic cardiovascular diseases, IDF, metabolic syndrome, NCEP ATP III To perform inferential analysis, we used the chai square test for categorical variables and the independent t-test for continuous variables.Kappa agreement coefficient was carried out to assess concordance between MetS definitions.

| Ethical considerations
This project was reviewed and approved by the ethics committee of the Kerman University of Medical Sciences with the licence number IR.KMU.AH.REC.1397.170.Also, informed consent was obtained from all the participants.
We used the AHA calculator for assessing cardiovascular risk; using the t-test we realised that the ASCVD risk score was significantly higher in both groups with MetS (p − value < .001),but the difference between those with MetS and those without it was higher in the NCEP ATP III group.Patients with MetS consistent with NCEP ATP III had higher ASCVD risk scores than those with IDF (10.63 ± 10.989 vs. 9.50 ± 9.357; Table 4).
The NCEP ATP III demonstrated superior specificity across all ASCVD risk score groups compared to the IDF criteria.While initially, sensitivity, accuracy, and positive and negative predictive values favoured IDF, as the ASCVD risk scores increased, NCEP ATP III exhibited higher values for these parameters (Figure 1).
The agreement between IDF and NCEP ATP III was none to slight for all ASCVD risk scores (Cohen's Kappa <0.2) except for IDF in the group of ASCVD >30%, which revealed no agreement (Cohen's Kappa = 0).

| DISCUSS ION
We performed a cross-sectional study on 600 patients selected from the previously published cohort: KERCADRS.The ASCVD risk score was significantly higher in patients with MetS in both groups, but the difference was higher for the NCEP ATP III.Although both IDF and NCEP ATP III are weakly correlated with the ASCVD risk score, NCEP ATP III is slightly better at predicting ASCVDs, especially with the fact that, as the ASCVD risk score goes higher, the ability of IDF decreases.
Zibaeenezhad et al. 17    this can increase the number of patients diagnosed with MetS in IDF and increase the number of higher-risk patients in NCEP ATP III.Additionally, in our study, NCEP ATP III had higher specificity in all the groups; it also exhibited better performance in terms of sensitivity, accuracy, and positive and negative predictive values.

MetS is closely related to several morbid conditions including
ASCVDs and poor kidney function.
Organization (WHO), European Group of Insulin Resistance (EGIR), International Diabetes Federation (IDF) and National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III); these definitions have shown different abilities. 7The first definition was proposed by WHO in 1998, which believed that insulin resistance and its surrogates, impaired glucose tolerance (IGT), and type 2 diabetes mellitus, are the essential components of MetS; other components consisted of raised blood pressure, hypertriglyceridemia or low HDL, obesity and microalbuminuria.In IDF's definition of MetS (2005), central obesity is the prerequisite of the MetS diagnosis.The IDF has a particular emphasis on waist measurement as a simple screening tool.The NCEP ATP III (2001) had a different approach; neither insulin resistance nor central obesity were the essential part of the MetS definition; instead, the NCEP ATP III definition approached MetS as a collection of metabolic factors and remained more silent regarding the exact pathophysiology. 8ome studies[9][10][11][12] have assessed different definitions, but controversies still remain.Although the main components of MetS in different criteria are the same, the existence of some critical differences and having different thresholds have caused disparities between the results of different definitions.

ulation aged 15 -
75 years living in Kerman, Iran (the largest city in south-eastern Iran with a population of about 780,000 people) by Physiology Research Center of Kerman University of Medical Sciences (KPRC) in two phases: September 2009-December 2011 and October 2014-September 2018.Inclusion criteria in the present analysis included age 40-79 years, awareness of participation in the study and completing the questionnaire thoroughly and flawlessly.
compared the ability of four definitions of MetS including World Health Organisation (WHO), NCEP ATP III, AHA and IDF in predicting 10-year ASCVD risk in 7225 patients; they used both ASCVD risk score and Framingham risk score (FRS) for predicting the risk of developing ASCVD in the future; the number of patients diagnosed with WHO criteria was the lowest (N = 1676); the difference between patients with and without MetS was statistically significant in AHA, WHO and NCEP ATP III, but the difference was not significant in IDF; they concluded that IDF is not an appropriate criterion for discrimination of patients with and without MetS.TA B L E 1Defining ATP III and IDF as the definitions of metabolic syndrome.
31 characterised arterial ageing by increasing arterial stiffness and measured it with pulse wave velocity (PWV).Participants with healthy vascular ageing (HVA) had significantly lower levels of cardiovascular risk factors including blood pressure, lipids, glucose, obesity, diabetes mellitus, hypertension, and the MetS.They estimated that HVA participants were generally up to 14 years biologically younger than those with higher PWV in terms of vascular health (5.8 ± 0.5 m/s vs. 7.4 ± 1.4; p − value< .0001);they also had lower risk factor levels.These changes can potentially contribute to greater CVD risk as in a systematic review by Ben-Shlomo et al.32 on 17,635 participants, PWV could reveal itself as an important factor in predicting ASCVDs.PWV was significantly associated with coronary heart disease, stroke, and cardiovascular events in multiple analyses (p − value < .001).Adding PWV to indices could even improve their risk prediction ability in some subgroups (13% for 10-year CVD risk for intermediate risk).Additionally, MetS is associated with poorer kidney function.Obesity, as a pivotal component of MetS, predisposes patients to diabetic nephropathy, hypertensive nephrosclerosis, and focal and segmental glomerular sclerosis; it also plays principal roles in the development and progression of chronic kidney disease (CKD).Also, albuminuria is an important risk factor for ASCVDs, and microalbuminuria is an early manifestation of kidney injury and diabetic nephropathy in MetS.Altered levels of adipokines such as leptin and adiponectin, oxidative stress, and inflammation are several obesityand MetS-induced mechanisms involved in changes in renal physiology and metabolism.33Endothelial dysfunction marks a crucial early stage in the initiation and advancement of atherosclerosis, playing a significant F I G U R E 1 Diagnostic ability of ATP III and IDF in different categories of ASCVD risk scores.
Prevalence of underlying condition among participants.
ASCVD risk score in subjects with and without MetS in the two definitions.
26ai et al.18conducted a study to investigate the ability of the adjusted ATP III by the American Heart Association and the National Heart, Lung, and Blood Institute (ATP III/AHA/NHLBI) and IDF in predicting ASCVD development.They used brachial-ankle pulse wave velocity as their ASCVD risk assessment tool; their results showed that the performance of the ATP III/AHA/NHLBI is superior to the IDF.Moreno et al.19performed a study to evaluate the clinical performance of WHO, NCEP-ATP III, IDF, AHA/NHLBI, Joint Interim Statement (JIS), and Latin American Diabetes Association (ALAD).21foundthat the prevalence of MetS in Turkey was 34.6% and 28.8% according to IDF and NCEP ATP III, respectively.Salas et al.22in Mexico used the census definition (IDF/NHLBI/AHA/WHF/IAS/IASO)23; they found the prevalence of MetS to be 54.8%.In the United States, Hirode and Wong24used NCEP ATP III and declared the prevalence of MetS to be 34.8%.In Iran, Zibaeenezhad et al.17performed a cross-sectional analysis Marbou and Kuete 25 investigated the prevalence of MetS and its components in Cameroon; they found that 32% of 604 patients had MetS, and 58.16%, 6.13%, 3.48% and 11.42% had hypertension, diabetes mellitus and current and former history of smoking; also, decreased HDL (82.78%) and increased LDL (22.85%) were the most and least common forms of dyslipidemia.Biadgo et al.26andTamiru and Alemseged 27 worked on the prevalence of MetS and its components in patients with type 2 diabetes mellitus.Biadgo et al.found out that the difference between participants with and without MetS is significant in NCEP ATP III, but the difference was not significant in IDF and declared IDF as an inappropriate tool for diagnosing MetS.The smaller difference in IDF and the larger difference in NCEP ATP III seems to make a difference in the number of patients diagnosed with MetS; as reflected in Moreno et al. study, Topouchian et al. 29 performed had thicker, stiffer or less distensible, and wider large arteries than participants without MetS.There are differences regarding the effects of different MetS components on arterial changes; any combination of altered glucose tolerance, elevated blood pressure, and elevated TG significantly increased age-associated arterial alterations.They believed that having MetS accelerates age-related arterial changes, and this is true even in older patients.Nilsson et al.